The regulatory region of the neuronal nicotinic acetylcholine receptor alpha 2 subunit gene, which contains six copies of the octamer-related sequence CCCCATGCAAT, is activated by the Brn-3b POU family transcription factor but not by the closely related factors Brn-3a and Brn-3c. This effect is in contrast to the previously documented inhibitory effect of Brn-3b on octamer-containing promoters that are activated by Brn-3a and Brn-3c. Activation of the alpha 2 gene by Brn-3b requires that both the POU domain and other N-terminal sequences are derived from Brn-3b and is dependent on the intactness of the alpha 2 gene regulatory region, being lost in truncated derivatives containing one, two, or four copies of the octamer-related sequence. Surprisingly, however, these truncated derivatives are activated by Brn-3c. These effects are discussed in terms of both the influence of the target sequence and its context in the promoter on activation by the various forms of Brn-3 as well as of the processes that restrict expression of the alpha 2 subunit gene to a few cells in the nervous system.